Biology subjects

Leong, M.

Publications and source records attributed to Leong, M..

7 recordsLinked to original sources

bioRxiv2025

NTX250: A Modular mRNA-Based Immunotherapy Platform for HPV-Associated Cancers with Broad Applicability.

Infection with high-risk human papillomavirus (HPV) is a key driver of multiple HPV-associated malignancies, including cervical intraepithelial neoplasia (CIN), oropharyngeal, head and neck, and anogenital cancers. Despite the high efficacy of prophylactic HPV vaccines, a substantial population remains at ongoing risk due to issues related to vaccine accessibility, awareness, or personal choice. Current treatments, such as the loop electrosurgical excision procedure (LEEP), address lesions but do not eliminate persistent HPV infection and are associated with potential complications. Moreover, individuals treated for HPV-related disease are at increased risk for subsequent HPV-associated malignancies. These factors underscore an urgent need for effective, non-invasive therapeutic strategies capable of targeting and eradicating persistent HPV infections. Here we introduce NTX250, an innovative mRNA-based therapeutic platform designed to deliver HPV type 16 (HPV16) E6-E7 antigens, combined with immunomodulators human interleukin-12 (IL-12) p70 and engineered human LIGHT (LIGHT). The mRNAs are co-delivered via lipid and ionizable peptoid nanoparticles referred to as Nutshell formulation for intralesional administration. Our preclinical evaluation demonstrates that localized delivery of NTX250 in HPV16-transformed tumor-bearing models results in complete tumor regression and the induction of durable, antigen-specific immune memory. Moreover, this modular mRNA nanoparticle approach combining tumor-specific antigens and immunomodulators is adaptable beyond HPV, with potential applications targeting neoepitopes or other tumor-associated antigens, thus offering a versatile platform for immunotherapy across a broad range of indications. These findings highlight the potential of this strategy as a broadly applicable, non-surgical immunotherapeutic capable of inducing robust and specific anti-tumor responses.

immunology↗

bioRxiv2025

The Building Blocks of Early Land Plants: Glycosyltransferases and Cell Wall Architecture in the model liverwort Marchantia polymorpha

The liverwort Marchantia polymorpha has emerged as an important plant model for developmental studies and may become central to elucidate the complex process of cell wall polysaccharide biosynthesis. This study comprehensively analyses the composition and structure of cell wall glycans across eight different M. polymorpha tissue types. We show that while the cell walls largely mirror known land plant cell wall composition, they also exhibit some unique characteristics. For example, -(1,5)-arabinan was prominently present in the sporophyte tissue, which may indicate a specialised role in this life stage. Furthermore, M. polymorpha cell walls displayed a remarkably low overall pectin content, yet the abundance of pectic arabinan in sporophytes hint at its putative role in the evolution and complexity of spermatophyte cell walls. Through comparative analyses of glycosyltransferase (GT) families across plant species, we found that M. polymorpha has a diversified GT repertoire compared for example, to the model plant Arabidopsis thaliana, indicating uniqueness in its cell wall biosynthesis pathways. To support research underpinning cell wall biosynthesis, we developed a Gateway compatible compendium of 93 M. polymorpha GTs, providing a valuable resource for genetic and functional studies. Our study thus works as a foundation to drive new insights into cell wall evolution, structure and function across the plant kingdom.

plant biology↗

bioRxiv2024

Persistence and Free Chlorine Disinfection of Human Coronaviruses and Their Surrogates in Water

The COVID-19 pandemic illustrates the importance of understanding the behavior and control of human pathogenic viruses in the environment. Exposure via water (drinking, bathing, and recreation) is a known route of transmission of viruses to humans, but the literature is relatively void of studies on the persistence of many viruses, especially coronaviruses, in water and their susceptibility to chlorine disinfection. To fill that knowledge gap, we evaluated the persistence and free chlorine disinfection of human coronavirus OC43 (HCoV-OC43) and its surrogates, murine hepatitis virus (MHV) and porcine transmissible gastroenteritis virus (TGEV), in drinking water and laboratory buffer using cell culture methods. The decay rate constants of human coronavirus and its surrogates in water varied depending on virus and water matrix. In drinking water prior to disinfectant addition, MHV showed the largest decay rate constant (2.25 day-1) followed by HCoV-OC43 (0.99 day-1) and TGEV (0.65 day-1); while in phosphate buffer, HCoV-OC43 (0.51 day-1) had a larger decay rate constant than MHV (0.28 day-1) and TGEV (0.24 day-1). Upon free chlorine disinfection, the inactivation rates of coronaviruses were independent of free chlorine concentration and not affected by water matrix, though they still varied between viruses. TGEV showed the highest susceptibility to free chlorine disinfection with the inactivation rate constant of 113.50 mg-1 min-1 L, followed by MHV (81.33 mg-1 min-1 L) and HCoV-OC43 (59.42 mg-1 min-1 L). ImportanceThis study addresses an important knowledge gap on enveloped virus persistence and disinfection in water. Results have immediate practical applications for shaping evidence-based water policies, particularly in the development of disinfection strategies for pathogenic virus control.

microbiology↗

bioRxiv2021

Directed Evolution of AAV Targeting Primate Retina by Intravitreal Injection Identifies R100, a Variant Demonstrating Robust Gene Delivery and Therapeutic Efficacy in Non-Human Primates

Targeted AAV vectors are needed for safe and efficient delivery to and transduction of specific tissue target(s) in patients. Effective intravitreal delivery for retina gene therapy is not feasible with wildtype AAV. We employed directed evolution in nonhuman primates (NHP) to discover an AAV variant (R100) for intravitreal treatment of multiple target cells in the primate retina. R100 demonstrated superior transduction of human retinal cells compared to wildtype AAV. Furthermore, three R100-based gene therapeutics demonstrated safety, delivery, and durable pan-retinal expression of intracellular or secreted transgenes throughout the NHP retina following intravitreal administration. Finally, efficacy of R100-mediated delivery of therapeutic transgenes was demonstrated in patient-derived retinal cells (monogenic diseases) and in an NHP model of pathogenic retinal angiogenesis.

bioengineering↗

bioRxiv2020

The self-peptide repertoire plays a critical role in transplant tolerance induction

While direct allorecognition underpins both solid organ allograft rejection and tolerance induction, the specific molecular targets of most directly-alloreactive CD8+ T cells have not been defined. In this study, we used a combination of genetically-engineered MHC class I (MHC I) constructs, mice with a hepatocyte-specific mutation in the class I antigen-presentation pathway and immunopeptidomic analysis to provide definitive evidence for the contribution of the peptide cargo of allogeneic MHC I molecules to transplant tolerance induction. We established a systematic approach for the discovery of directly-recognised pMHC epitopes, and identified 17 strongly immunogenic H-2Kb-associated peptides recognised by CD8+ T cells from B10.BR (H-2k) mice, 13 of which were also recognised by BALB/c (H-2d) mice. As few as five different tetramers used together were able to identify a high proportion of alloreactive T cells within a polyclonal population, suggesting that there are immunodominant allogeneic MHC-peptide complexes that can account for a large component of the alloresponse.

immunology↗

bioRxiv2020

Novel Immunoglobulin Domain Proteins Provide Insights into Evolution and Pathogenesis Mechanisms of SARS-Related Coronaviruses

A novel coronavirus (SARS-CoV-2) is the causative agent of an emergent severe respiratory disease (COVID-19) in humans that is threatening to result in a global health crisis. By using genomic, sequence, structural and evolutionary analysis, we show that Alpha- and Beta-CoVs possess several novel families of immunoglobulin (Ig) domain proteins, including ORF8 and ORF7a from SARS-related coronaviruses and two protein groups from certain Alpha-CoVs. Among them, ORF8 is distinguished in being rapidly evolving, possessing a unique insert and a hypervariable position among SARS-CoV-2 genomes in its predicted ligand-binding groove. We also uncover many Ig proteins from several metazoan viruses which are distinct in sequence and structure but share an architecture comparable to that of CoV Ig domain proteins. Hence, we propose that deployment of Ig domain proteins is a widely-used strategy by viruses, and SARS-CoV-2 ORF8 is a potential pathogenicity factor which evolves rapidly to counter the immune response and facilitate the transmission between hosts.

microbiology↗

bioRxiv2019

Abbreviated assessment of psychopathology in patients with suspected seizure disorders

PurposePsychopathology is common in patients undergoing investigation for seizure-related disorders. Psychometric examination using self-report instruments, such as the SCL-90-R, can assist diagnosis. The SCL-90-R, however, is a lengthy instrument and might not be tolerated by all patients. We assessed several abbreviated forms of the SCL-90-R in patients undergoing video encephalographic monitoring (VEM).\n\nMethod687 patients completed the SCL-90-R and scores were computed for the full SCL-90-R and five abbreviated forms. Correlations and mean differences were computed between different forms. Classification accuracy was assessed via receiver operating characteristic (ROC) curves, and measurements models were examined using confirmatory factor analysis (CFA).\n\nResultsAll abbreviated forms were strongly correlated with the SCL-90-R for general psychopathology (r = .93 - .99), depression (r = .89 - .95), anxiety (r = .97 - .98), psychosis (r = .95 - .99), and obsessive-compulsive symptoms (r = .97). Classification performance was similar across forms for depression and anxiety, with high negative predictive values (.90 - .94) and lower positive predictive values (.34 - .38). Classification performance for psychotic and obsessive-compulsive disorders was poor. Differences were observed between the full SCL-90-R and its abbreviated forms across most domains (d = 0.00 - 0.65). The published measurement model was most strongly validated for the SCL-27, SCL-14, and the SCL-K-9.\n\nConclusionsThese five SCL-90-R abbreviated forms show high convergent validity with the full version. In patients undergoing investigation for seizure-related disorders, the BSI or BSI-18 are most appropriate where screening for both depression and anxiety is required. The SCL-K-9 is appropriate when only a single measure of global psychological distress is required. None of the instruments were able to detect psychotic or obsessive-compulsive symptoms with great accuracy. Caution should be exercised when making direct comparisons across the different forms.

neuroscience↗